Radiotherapy in cancer pain management

Radiotherapy in cancer pain management J.E Nebbia, C. Ortholan, J.R

Gerard 1

Centre Antoine-Lacassagne, Nice, France

Epidemiology of pain in oncology and radiotherapy

will remain free from pain. In 80% of patients, the primary cancer is originating from breast, lung, kidney and prostate [8]. The median survival time after appearance of bone metastases is between 2 and 4 years for patients with breast, prostate and thyroid cancers. The prognosis for lung cancer is shorter, usually less than one year. Between 5% and 40% of patients will be alive at 5 years (Table 1). The metastases may involve vertebrae, long bones, the pelvis or skull [9]. Approximately 65% of patients with skeletal disease suffer from bone pain [10]. Associated to pain, cancer patients also suffer from symptoms like anorexia, asthenia, nausea, vomiting, insomnia, and all these symptoms have to be treated contemporarily [11]. Other main indications of radiotherapy in cancer pain management are fractures due to bones metastases, spinal cord compression, multiple myeloma, brain metastases, primary mmours (e.g. pancreatic carcinoma, Pancoast tumours, recurrent pelvic mmours) and benign diseases (e.g. peritendinitis, heel spur, degenerative osteoarthritis), which will not be covered in this review. It is important to remember that if radiotherapy is effective to control pain, it can be also responsible for painful conditions like osteoradionecrosis of the mandible, soft tissue necrosis of the oral cavity or anal canal, and radiation plexopathy.

Pain is a common symptom in the natural history of cancer. It can be present during the initial phase of the disease, especially in certain tumour locations (e.g. bone, central nervous system, pancreas, and lung). It is more frequent in locally recurrent or metastatic disease. Most cancer patients experience pain, usually of moderate to severe intensity, and also have a number of distinct pain types. The commonest situation responsible for pain is bone metastases. In metastatic or recurrent malignant disease, pain of different intensity is present in 50-70% of cases, of which 75% are directly attributable to the malignancy [1-5]. Careful clinical evaluation of pain is an essential part of the global management of the cancer patients; this can be difficult in some special situations, as in elderly patients. An objective measurement of pain intensity is necessary, and can be performed most of the time with a visual analgesic scale [6]. The management of pain is a team approach between specialists in chemotherapy, radiotherapy, surgery and anaesthesiology and supportive care, but also psychologists and physiotherapists. For example, the conventional symptomatic treatment of metastatic bone pain requires the use of multidisciplinary therapies, such as analgesic medication (from level 1 to level 3, non-opioid and opioid analgesics, and also tricyclic antidepressants, anticonvulsive, psychotropic drugs, non-steroidal anti-inflanm~atory drugs, corticosteroids, bisphosphonates) in association with radiotherapy, chemotherapy or hormonotherapy depending on the primary site [7]. Radiotherapy is playing an important role in pain control in association with these other approaches. In a standard radiotherapy department, approximately 15% of patients are referred for pain relief. The most frequent clinical situation is to provide pain relief for painful bone metastases and for threequarters of patients who achieve pain relief, half

Pathophysiology of cancer pain Cancer pain is due to different mechanisms, but most of the time it is related to direct mmour infiltration. These somatic and visceral pains result from activation of nociceptors by mmour infiltration of tissues, and from secondary inflammatory changes with release of algesic chemicals that act to sensitize nociceptors [14]. The management of such pain is performed through treatment targeted at the mmour

With the contribution of A. Courdi, K. Benezery, R.J. Bensadoun, RY. Bondiau, J. Darcourt and O. Thomas, Department of Radiation Oncology and Department of Nuclear Medicine.

87

88

J.E Nebbia et aL

Table 1 Results of two recent randomized trials comparing single-fraction radiotherapy vs. multiple fractions Trial

Schedule

pts

Pain relief

Complete response

Progression

Retreatment

Pathological fracture

Bone Pain Trial Working Party [12], 1999

1 × 8 Gy 5 × 4Gy 10×3Gy

383 378

78% 78%

57% 58%

34% 30%

23% 10% p <0.001

7 patients 9 patients p-0.2

Dutch Bone metastasis study [13], 1999

1 × 8Gy 6 × 4Gy

585 586

72% 69%

37% 33%

52% 46%

25% 7% p < 0.0001

24 patients (4%) 10 patients (2%) p < 0.05

(chemotherapy, surgery, or radiotherapy) and analgesic drugs (non-opioid, opioid) [15]. Deafferentation pain is maybe another mechanism and is related to injury and infiltration of peripheral nerves [15]. This pain is difficult to control, and may continue after treating the cause. The pathophysiology of pain due to bone invasion is complex, and can be due to nerve compression, or muscle contractions. The proliferation of malignant cells increases the pressure in the bone, leading to increased pain. In such cases, the main mechanism is somatic pain by nociception. Radiotherapy on this proliferation is very effective, by reducing the number of mmour cells, which decreases pressure and pain in the bone [16]. In some patients, the rapid pain response to the radiotherapy is related to inactivation or killing of inflammatory cells.

Radiotherapy of bone pain Bone metastases Single-fraction technique

Approximately 65% of patients with skeletal metastatic disease suffer from significant pain. One-third of patients with breast or prostate cancer and two-thirds of those with lung cancer will develop metastatic bone disease [17]. It is very common in a radiotherapy department where it can represent 10 to 20% of treatments. Radiotherapy is considered as a very effective treatment to control pain. A decade ago, the standard technique for bone metastases was an accelerated schedule of 5-10 fractions, delivering 20 Gy/5 fractions or 30 Gy/10 fractions over a period of 1 or 2 weeks [18]. Many recent randomised trials have compared such accelerated fractionated schedule with a single fraction delivering usually 8 Gy. The randomised trial of the Bone Pain Trial Working Party, comparing a single-fraction of 8 Gy with multifraction doses, analysed overall survival, time to

progression, time to first pain relief and complete pain relief (Table 1). In this trial, 681 patients were included between 1992 and 1997 with a follow-up over one year. The single-fraction delivered 8 Gy in 1 fraction over 1 day. Most of the patients (98%) allocated to a multifraction schedule received 20 Gy in 5 fractions over 5 days. The others (2%) received 3 0 G y in 10 fractions over 10 days. Overall 78% of patients who could be evaluated experienced pain relief in both groups, and 57% in the single-fraction group vs. 58% in the multifraction group experienced a complete response. However, 23% of patients randomised to the single-fraction schedule were retreated, compared to 10% on the multifraction regimen (p < 0.001). No difference in time to progression and overall survival was observed [12]. The Dutch Bone Metastasis Study randomised 1171 patients with painful bone metastasis to receive either 8 Gy in 1 fraction or 24 Gy (4 Gy in 6 fractions). Both regimens were equivalent in term of palliation: rate of response and of complete response were respectively 69% and 33% in the multifraction group and 72% and 37% in the single-fraction group. Median time to pain progression was 24 weeks in the 4 Gy × 6 arm and 20 weeks in the 8 Gy × 1 arm. There was an effect of primary tumour type: breast cancer did better than prostate, lung or other cancer patients, with median time to progression of 36 weeks, 20 weeks, 10 weeks and 8 weeks, respectively (p <0.0001). Retreatment was 25% in the 8 Gy × 1 group and 7% in the 4 Gy × 6 arm (Table 1) and it took place at an earlier stage in the 8 Gy × 1 group. More fractures were observed in the single-fraction than in the multifraction schedule (4% vs. 2%, p < 0.05) [13]. A study evaluated remineralization of lyric lesions after radiotherapy, using CT density measurement. After 6 months of follow up, bone density was significantly increased by an average of 173% after 3 0 G y in 10 fractions, compared with an average increase of 120% after 8 Gy in single fractions [19].

Radiotherapy in cancer pain management

The meta-analysis of Wu has reviewed the published literature on dose fractionation in local radiotherapy, to determine the schedule for painful bone metastases between 1966 and 2000. It divided published reports into three categories: comparison of single-fraction vs. single-fraction, comparison of single-fraction vs. multifraction radiotherapy, and comparison of different doses of multifraction radiotherapy. Analysis of trials with different single-fraction doses showed that response rates were lower with 4Gy, but were similar with 6 Gy and 8 Gy, suggesting the absence of dose-effect relationship for total doses >4Gy. No difference was found between different fractionation schedules (single-fraction vs. multifraction or multifraction vs. multifraction). No dose~esponse relationship, no difference among dose-fractionation schedules, no median duration of response (between 11 and 24 weeks), and no difference of toxicities were found between different schedules. The median time for pain relief after treatment was 3 weeks and the median actuarial duration of pain control was between 4 and 5 months, with two thirds of the patients experiencing complete pain control. This review concluded that it was recommended to use single-fraction dose radiotherapy with 8 Gy for painful bone metastases [20]. Pain flare following radiotherapy has been reported. A prospective evaluation of pain in 88 patients showed that 14% of patients who received a single fraction treatment had a pain flare on day 1 and 15% of patients who received multiple-dose fractions had a pain flare on day 1 but remaining in the range of 10-20% during the treatment [21 ]. In conclusion, randomized trials showed no significant difference between single and multiple fractions schedules for painful bone metastases, and confirmed the efficacy of the short-term schedule of 8 Gy in 1 fraction. Retreatment after irradiation Both the Dutch Bone Metastasis Study and the Bone Trial Working Party showed a significantly higher rate ofretreatment in the single-fraction arm, but this could be due to a bias: it is considered more dangerous for radiation toxicity to give a second irradiation after 20 or 30Gy, than after a single dose of 8 Gy and physicians are more willing to retreat after a single fraction. Analysis of the retreated patients in the Dutch Bone Metastasis Study showed that response to retreatment was 66% in the single-fraction group and 46% in the multifraction group (p=0.12, ns). Time to response was not different in both groups, but the mean duration of remission was substantially longer in

89

initial single-fraction patients (16 weeks vs. 8 weeks). Prostate cancer experienced the lowest response rate of retreatment (43%). No major difference in toxicity was observed. The authors conclude that with or without the effect of retreatment, single-fraction and multifraction radiotherapy provide equal palliation for painful bone metastases [22]. Cost analysis In a radiotherapy department, the cost model results from three cost categories: series, fractions and Gy. A cost analysis of the Dutch trial was performed. The cost for a single-fraction schedule includes the cost per series, the cost per fraction, and 8 times the cost per Gy. In the same way, the cost of a multifraction schedule delivering 24Gy over 6 fractions includes the price of one series, 6 times the price per fraction, and 24 times the cost per Gy. In this trial, the single-fraction schedule is less expensive than the multifraction one [23]. Controversies in single-fraction schedule Pain relief, overall survival, quality of life and toxicity are equivalent between single- and multifraction radiotherapy. Moreover, the single fraction is more convenient to patients with metastatic bone pain, with less time spent in hospital, fewer constraints, and it is easier to implement into a radiotherapy department. However, the higher rate of fracture and retreatment in the single-fraction schedule cannot be ignored. Considering advantages and disadvantages of singleand multifractionation schedule, what could be the patients' choice? A study tried to assess an answer to this question, offering to patients the choice between two fractionation schedules: 24Gy in six fractions vs. 8Gy in one fraction. Sixty-two patients were informed on advantages and disadvantages of these two schedules and were asked to choose a fractionation schedule, to give a reason for their choice and to indicate the level of satisfaction with being involved in decision making. 85% preferred 24 Gy in 6 fractions over 8 Gy in one fraction (p < 0.0005). Multifractionation was chosen for the lower retreatment rate (92%) and fewer fractures (32%). Single-fraction was chosen for cost (11%) and convenience (89%) [24]. Another study evaluating patient' s preference between 20 Gy in 5 fractions vs. 8 Gy in one fraction in 101 patients showed opposite results. 72% preferred the singlefraction schedule [25]. In conclusion, single-fraction radiotherapy (8 Gy in one fraction) can be considered in most patients as the standard palliative treatment for cancer patients with painful bone metastases. When large volumes (including small bowel or lung)

J.E Nebbia et al.

90

GLENOID CAVITY OF THE SCAPULO-HUMERAL JOINT METASTASIS

FEMORAL

Techniques: • patient supine

Techniques: • patient supine.

• two parallel opposed fields AP/PA

• two parallal opposed fields AP and PA.

• photon X _>6 MV

• photon X> 6 M ~ Simulation: • simulator or 2D dosimelric display.

Simulation: simulator or 2D dosimetric display. Field:

• 8 cm x 12

Dose:

METASTASES

cm.

• 8 Oy in 1 fraction, with equal loading between both fields (4 Cry + 4 Gy)

Field:

* 1 0 c m x 16 cm.

Dose:

• 8 Gy in 1 fraction, with equal loeding between both fields (4 Gy + 4 Gy) calculated at mid-plane.

calculated at mid-pLane.

• 13 Cry in 2 fi'actions, with equal loading between both fields (6.5 Gy + 6.5 Gy)

Other possible technique : one single anterior field with photon X>I 5 MV, and dose of 8 Cry

calculated at mid-plane.

calculated at the level of the given dose (close to 3 cm).

• doe to the diameter of the hip (> 14 cm), a single anterior field is not

Field of irradiation on simulator:

recommended. Field of irradiation on simulator:

Bone me

NB: Nail surgery can be proposed, due to the high risk of fracture.

Fig. 1.

Fig. 2.

LUMBAR BONE METASTASES Techniques:

* patient supine.

Field:

• two parallel opposed fields A P and PA. • photon X > 8 MV. Simulation:

• one vertebra above and below the metastatic vertebra. • 10 c m x 9 cm.

Dose:

• simulator or 2D dosimct~ic display.

• 8 Cry in 1 fzaction, with equal loading between both fields (4 Gy + 4 Gy) calculated at midplane. 2D dosimetric display with the isodoses o f irradiation:

Field o f irradiation on simulator:

:::::::::::::::::::::::::::::::::::::::::::::::::::: :x ' ==......... ================================ :; :::::::::: ....... -::: :,: :.:~,x 4~?ii?i~ii::~:i:i:i --j,

~>)

Bone metastasis

"?':

~

N

.-.-A.-.-..--.-+;,

:;,::::

i ..... NB: C T can be useful to assess the extension o f the

....

J

NB: a different loading o f the irradiation can be proposed to slightly reduce the dose in the

vertebral metastases in the surrounding soi~ tissues, which

abdomen (posterior field 5 Gy, anterior field 3 Cry). It should be noted that the anterior

can lead to an increase in the width o f the field.

part o f the vertebra is at the midplane.

F i g . 3.

Radiotherapy in cancer pain management SPINAL CORD COMPRESSION WITH EPIDURAL METASTASIS

RIB METASTASIS

Techniques: • patient supine.

Techniques:

• patient supine. • one single lateral field.

• two parallel opposed fields A P and PA.

Simulation: Field:

• photon X > 8 M V .

• elect~ns: 12 MeV.

• simulator or 2D dosimetric display.

• depth of 3 era.

Simulation:

• two vertebras above and below the metastatic vertebra. • 16 c m x 9 cm.

Dose:

91

• 8 Cry in I fraction, with equal loading b e t w e e n both fields (4 G y + 4 Cry) calculated at mid-plane or:

• simulator or 2D dosimetric display.

Fiekl:

• 7 can x 6 cm.

Dose:

• 8 G y in 1 fraction, calculated on the 90% isodos¢.

2D dosimctfic display with the isodoses o f irradiation:

• 20 Gy in 5 fractions, with equal loading between both fields (2 G y + 2 Gy) calculated at mid-plane, can also be proposed.

Field o f irradiation on simulator:

~ ~".i;'".'. .......... ~ ~~ j

.......

Ribm~t.si~

£:: .....

Epiduralmetastasisl

NB: it must be remembered that the dose dism'bution o f electrons in air is not very accurate with most o f the software used for treatment planning, the dose in the lung is not known with a e c . u ~ y with e l e e ~ n s .

Fig. 6. NB: M R 1 shows an ¢pidural metastafis-extending between T6 to T8.

Fig. 4. SACRO-ILIAC J O I N T M E T A S T A S I S Technioues:

* patient supine. • three fields: two parallel lateral opposed and one posterior (wedges). • photon X > 8 MV.

Simulation:

2D dosimetric display with the isodoses of irradiation:

• simulator or 2D dosimetric display.

Field:

* 11 em x 9 om

Dose:

• 20 Gy in 5 liactions: 1.5 Gy for each lateral fields, and I Gy for the posterior one .

:°::'

..~:.

::. • .~

NNl/

"N

.

.

.

.

.

.

.

.

.

" ' ".qi:*:i:,x.""

"U :""~

"iiii: '"

. .

::::::: "%iiiiiii:=e

":....

L :

..-.

Fig. 5.

are included in the irradiation fields, especially in flail, debilitated patients, it can be safer to use a flactionated schedule. Patients should be informed and involved in therapeutic decision. Dose per fraction of 4 or 5 Gy can be given in such a case for a total dose of 10-20 Gy. Some treatment techniques for bone metastases are presented in Figs. 1 through 6.

Neuropathic pain due to bone metastases None of the studies evaluating radiotherapy for painful bone metastases classified pain to underlying aetiology (e.g. mechanical vs. non-mechanical, neuropathic component). Neuropathic pain refers to a pain or dysaesthesia with a radiating cutaneous component in the distribution of spinal nerves or peripheral

92

JE Nebbia et aL Table 2 Results of retrospective analysis ofRades et al. [27], comparing 5 schedules of radiotherapy in spinal cord compression Schedule

8 Gy: l×8Gy

20 Gy: 5×4Gy

30 Gy: 10×3Gy

30 Gy: 15 × 2.5Gy

40 Gy: 20 × 2 G y

Patients

261

Motor function improved

26%

Post treatment ambulatory rate In field recurrence at 2 years

279

274

233

257

28%

27%

31%

28%

ns

69%

68%

63%

66%

74%

ns

24%

26%

14%

9%

7%

<0.001

nerves. A recent study randomised 272 patients ro receive 8 Gy in one fraction or 20 Gy in 5 fractions. Overall response rare was 53% and 61% for single and multiple fractions respectively. Time ro treatment failure was 2.4 vs. 3.3 months. Although ir did nor achieve statistical significance, single-fraction was nor shown ro be as effective as mulriplefracrion. The authors conclude rhar 20Gy in 5 fractions should be recommended for neuroparhic pain due ro bone metastases [26]. Spinal cord compression In the case of spinal cord compression, neurological deficit with the risk of paraplegia is the main issue. Surgery and radiotherapy are effective treatments. Radiotherapy is aimed ar controlling cancer cells, usually infiltrating the epidural tissue. If pain is present, ir can be due ro direct bone invasion from a metastatic, or primary rumour, or perineural infiltration. Radiotherapy is playing an important role ro control pain, often in an emergency situation, and prevent evolution toward total paraplegia. The optimal treatment for patients wirh metastatic spinal cord compression is still being debated. Rades retrospectively evaluated several schedules: 1 × 8 Gy, 5 × 4 G y , 1 0 × 3 G y , 15×2.5Gy, 2 0 × 2 G y . These five radiotherapy schedules provided similar functional outcome and post-treatment ambulatory rare (Table 2). 26% of patients who were nor ambulatory before radiotherapy regained the ability ro walk [27]. To minimize treatment rime, the authors recommend 1 × 8 Gy for patients with poor predicted survival and 10 × 3 Gy for other patients. The short course regimen of 8 Gy in one fraction was specifically evaluated in 199 patients with spinal chord compression. 27 patients had improved motor function, 26% regained walking ability and 29% of long-term survivors (>12 months) needed re-irradiation [28]. Only one randomized trial compared two schedules of fracrionarion in metastatic spinal cord compression. Ir included 276 patients with a short life expectancy

p-value

randomly assigned ro receive a short-course radiotherapy (2 × 8 Gy) or a split-course radiotherapy (3 × 5Gy; 5 × 3Gy). No significant difference in response, duration of response, survival or toxicity was found between the two arms. After radiotherapy, 56% of patients in the short course and 59% of patients in the split course had back pain relief, 68% and 71% were able ro walk, and 90% and 89% had good bladder function. The authors recommend the short course regimen [29]. An example of irradiation technique for spinal cord compression is presented in Fig. 4. Multiple myeloma Myeloma and plasma cell mmours are radio-responding mmours, bur the systemic nature of the disease in most patients limits the application of localized irradiation. In multiple myeloma, an effective palliation of pain control can be obtained by small fields and low doses of radiation. A retrospective study tried ro define the minimum effective radiation dose for durable pain relief in 101 patients with multiple myeloma irradiated in 306 sires. Symptom relief was obtained in 92% of sires receiving a total dose less than 10 Gy and 98% of sires receiving 10Gy or more. No dose response relationship could be demonstrated [30]. Radiotherapy seems ro be more effective during concomitant chemotherapy than without systemic treatment. A srudy of 70 patients showed rhar 80% of patients suffering from myeloma pain had complete pain relief with local radiotherapy and concurrent chemotherapy vs. 39% in patients receiving only radiotherapy [31]. Hemibody irradiation has been performed in the past for generalized pain due ro multiple sire involvement in multiple myeloma. A single fraction of 6 Gy is used for the upper body and 8 Gy for the lower body. Ir is rarely used today, due ro toxicity. Nowadays, most patients with multiple myeloma receive bisphosphonare. No clinical trial has compared radiotherapy with bisphosphonare in pain relief. Optimal uses of these two modaliries require further

Radiotherapy in cancer pain management

investigation, and a combined approach using the concept of additive effect and spatial cooperation should be investigated.

Radiotherapy of other painful cancers Brain metastases

Brain metastases are a frequent complication in patients with solid mmours. The incidence varies between 20% and 30% [32]. The most frequent primary tumours are breast and lung. The incidence and symptoms of brain metastases are increasing, due to improvement of neurodiagnostic imaging, and the increased survival. Brain metastases are associated with pain in 60% of patients, due to intra-cerebral pressure. This is the most frequent symptom because of the nature of tumour growth and its surrounding oedema. The choice of the most adequate treatment depends on different prognostic factors [33]: number of metastases, type of primary cancer, status of systemic disease, performance and neurological status, and patient' s age. When possible, surgery is the treatment of choice. The surgical treatment is recommended for the single, superficially located brain metastasis with intra-cranial pressure (ICP) in patients with good performance status. Radiosurgery can be performed when there is a small number of brain metastasis (up to 3). These treatments can be followed by whole-brain radiotherapy (WBRT) with an improvement of overall survival to 8-11 months [34,35]. In other patients, WBRT alone is recommended with a median survival extended to 3-5 months. The technique can be wholebrain irradiation, delivering 30 Gy in 10 fractions over two weeks, or a combination of whole-brain irradiation with a boost to the gross tumour. Radiosurgery (RS) is used when there are less than four brain metastases. It can be proposed for patients with inaccessible lesions or those with poor performance status. Overall survival is between 6 and 12 months [36,37]. For patients with good prognostic factors, RS can be used with WBRT. RS seems to be as efficacious as surgery to provide relief of neurological symptoms. RS can be an alternative to surgical resection. Corticosteroids are also very effective to palliate pain. Pancoast syndrome

Radiotherapy is the standard treatment of pancoast syndrome. Tumours of the superior pulmonary sulcus, called pancoast tumours, are rare. Non-small cell lung carcinomas represent the most frequent cause of

93

superior sulcus lesions, they represent 5% of all lung cancers. Pancoast mmours are presenting with constant pain, by invasion of the lower part of the brachial plexus, the intercostal nerves and the stellate ganglion (Homer's syndrome). The distribution is from the shoulder and the scapula to the ulnar part of the arm, the elbow and finally to the ulnar distribution of the forearm, and the small and ring fingers of the hand. In 1961 Shaw and Paulson [38] introduced preoperative radiotherapy (30 to 45 Gy in four weeks, including the primary tumour, mediastinum and supraclavicular region), followed by surgical resection. This radiosurgical approach became the treatment of choice for pancoast mmours, with a mean 5-year survival of approximately 30% [39]. Nevertheless, even if local disease control was achieved, distant relapses (brain, bones) were frequent. Neoadjuvant treatment using radiotherapy and chemotherapy before surgery, could increase the resectability of the pancoast tumour and pain control. Further chemotherapy could be proposed after surgery. The induction chemoradiation for Pancoast mmours improves the rate of complete resection and medium-tern1 survival [40]. The surgical goal is en-bloc resection of the chest wall, with removal of the upper lung lobe in continuity of the ribs, vertebral transverse process, subclavian vessels, T1 nerve root, upper dorsal sympathetic chain, and prevertebral muscles. Pancreatic carcinoma

Pancreatic cancer is a tumour with poor prognosis. Most patients with carcinoma of the pancreas are diagnosed in a non-resectable stage. The median survival in that stage is between 6 and 12 months. The main goal is to preserve quality of life, and reduce pain and complications due to local progression. Radiotherapy for pancreatic cancer is used to increase the median survival in patients with resectable or unresectable tumours. However, radiotherapy also has a palliative aim, by reducing the symptoms of local progression (gastro-intestinal obstruction, biliary obstruction, or splanchnic invasion). Pain affects most patients with pancreatic carcinoma. The incidence of pain varies between 50% and 97%. At a late stage of the disease, pain is present in nearly 90% of patients [41]. To control pain from locally advanced carcinoma of the pancreas, medical treatment, surgical procedure (surgical thoracoscopy), percutaneaous splanchnicectomy, or radiotherapy can be used. Radiotherapy can be given with external beam, or as intra-operative, or a combination of both [42,43]. The standard radiotherapy schedule consists of a total dose of

94

J.E Nebbia et aL

50 Gy, given in 1.8-2 Gy per fraction, over 5 weeks. Unfortunately, the radiotherapy treatment is limited by side effects to soft tissues, small bowel, liver and kidneys [44,45]. For patients excluded from standard concomitant chemoradiotherapy (age >75 years, local extension of the disease, hematologic defects) with unresectable disease, hypofractionated radiotherapy in pain relief is efficacious: 30 Gy in two weeks, 3 Gy per fraction, with a reduced need for analgesics [41]. Locally recurrent turnouts

Locally recurrent mmours, especially in the pelvis (rectum, uterus, and bladder) are associated with pain. Radiotherapy can be proposed with either curative or palliative intent, but in most cases it is efficient for pain relief. The dose and field size depend on the various clinical situations.

Metabolic radiotherapy using radiopharmaceuticals An alternative for delivering radiation to the skeleton is the use of systemic radiopham~aceuticals. Strontium-89 Chloride and Samarium-153 EDTMP are the most widely used. Strontium-89 Chloride is a bone-seeking compound concentrated in the bone during osteoblast-induced bone mineralization, which behaves biologically like calcium. Strontium-89 is a beta-emitting radioisotope, with a physical half-life of 50.5 days and a maximum energy of 1.46MeV. The usual therapeutic dose is 148MBq. It is avidly taken up by osteoblastic metastatic prostatic cancer. It can palliate metastatic bone pain, and is as effective as external beam radiation. The main complication is bone marrow depression, so it is contraindicated in myelosuppressed patients. Samarium- 153 is a radioisotope emitting beta particles, with a maximum energy of 0.8MeV. It has a physical half-life of 1.9 days. Samarium-153 is targeted to the bone by conjugation with a phosphonate compound (EDTMP: ethylene-diamine-tetramethylene phosphonic acid). Strontium-89 Chloride and Samarium-153 EDTMP are concentrated in bone proportionally to osteoblastic activity. The use of therapeutic radionuclides, which localize at metastatic sites, has been found to be an effective method for bone pain palliation, especially for multiple bone metastases. This treatment is mainly indicated for bone pain by prostate cancer metastases escaping to hormonotherapy. It is based on the injection of radioactive isotopes, which are taken up by bone

metastases. Pain relief rates with Strontium-89 Chloride range from 60% to 84% [46-48]. The mean time to pain relief is about one month. The mean duration of relief is about 6 months. Patients can be retreated after 3 months, due to the longer half-life. With Samarium153 EDTMP, pain relief is between 62% and 74% [49]. The mean duration of relief is about 4 months. The mean time to pain relief is usually shorter than with Strontium-89 Chloride (one week vs. one month), because the half-life of Sm153 is shorter. Patients can be retreated after two months. It remains possible to perform another external radiotherapy focalised on painful localisations, after treating the patient with internal approach.

Hemi-body irradiation In case of diffuse bone metastases in various bone segments, upper or lower hemi-body irradiation (HBI) has been proposed. In some patients, both upper and lower HBI can be performed with careful matching of the adjacent limit of the fields. The radiation is given through a large anterior posterior posterio~ anterior (A~PA) field to a dose of 6 Gy at mild pain. Pain relief is obtained in the majority of patients, but radiation toxicity can be important due to large volume irradiation (nausea, vomiting, diarrhea, and asthenia). With the development of modern medical analgesic treatment with opioids, HBI is becoming uncommon [50,51].

Conclusion Pain management is a key aspect of global care for cancer patients. Pain control is often a multidisciplinary task involving different medical specialists. Medical treatment and psychosocial support are playing an increasing role especially in patients with advanced disease. For localized pain, especially from bone metastases, origin radiotherapy is a single and efficient treatment. From randomized trials and evidence-based medicine it is, at the present time, recommended to deliver radiotherapy in a single- or few-fraction schedule. Radiation oncologists in collaboration with other specialists are playing an important role in palliating pain and improving the quality of life of cancer patients.

References 1 Davis MP, Walsh D. Epidemiology of cancer pain and factors influencing poor pain control. Am JHosp Palliat Care 2004, 21, 137 142.

Radiotherapy in cancer pain management

2 Twycross RG, Fairfield S. Pain in far-advanced cancer. Pain 1982, 14, 3 0 3 0 1 0 . 3 Cleeland CS, Gonini R, Hatfield AK, Edmonson JH, Blum RH, Stewart JA, Pandya KJ. Pain and its treatment in outpatients with metastatic cancer. N Engl J M e d 1994, 330, 592 596. 4 Larue F, Colleau SM, Brasseur L, Cleeland CS. Multicentre study of cancer pain and its treatment in France. BMJ 1995, 310, 1034 1037. 5 Vainio A, Auvinen A. Prevalence of symptoms among patients with advanced cancer: an international collaborative study. Symptom Prevalence Group. J Pain Symptom Manage 1996, 12, 3 10. 6 Boureau F, Marsiglia X, Demuynck B, Krulik M. Pain related to cancer. Different elements of evaluation. Presse Med 1997, 26, 1733 1739. 7 Ripamonti C, Fulfaro E Malignant bone pain: pathophysiology and treatments. Curr Rev Pain 2000, 4, 187 196. 8 Tubiana-Hulin M. Incidence, prevalence and distribution of bone metastases. Bone 1991, 12(suppl 1), $9-S10. 9 McQuay HJ, Collins SL, Carroll D, Moore RA. Radiotherapy for the palliation of painful bone metastases. Cochrane Database Syst Rev 2000, 2, CD 001793. 10 Elte JW, Bijvoet OL, Cleton FJ, van Oosterom AT, Sleeboom HR. Osteolytic bone metastases in breast carcinoma pathogenesis, morbidity and bisphosphonate treatment. Eur J Cancer Clin Oncol 1986, 22, 493 500. 11 Andersen G, Sjogern R Epidemiology of cancer pain. Ugeskr Laeger 1998, 160, 2681 2684. 12 Bone Pain Trial Working Party. 8 Gy single fraction radiotherapy for the treatment of metastatic skeletal pain: randomised comparison with a multifraction schedule over 12 months of patients follow-up. Radiother Oncol 1999, 52, 111 121. 13 Steenland E, Leer JW, van Houwelingen H, et al. The effect of a single fraction compared to multiple fractions on painful bone metastases: a global analysis of the Dutch Bone Metastasis Study. Radiother Oncol 1999, 52, 9 5 4 6 . 14 Payne R. Cancer pain: Anatomy, physiology, and pharmacology. Cancer 1989, 63, 2266 2274. 15 Payne R. Anatomy, physiology, and neuropharmacology of cancer pain. Med Clin North Am 1987, 7, 153 167. 16 Akaet LA, Boterberg T. Pain control by ionizing radiation of bone metastasis. Int J Dev Biol 2004, 48, 599 606. 17 Falkmer U, Jarhult J, Wersall P, Cavallin-Stahl E. A systematic overview of radiation therapy effects with skeletal metastases. Acta Oncol 2003, 42, 620 633. 18 Saarto T, Janes R, Tenhunen M, Kouri M. Palliative radiotherapy in the treatment of skeletal metastases. Eur JPain 2002, 6, 323 330. 19 Koswi S, Budach V. Remineralization and pain relief in bone metastases after different radiotherapy fractions (10 times 3 Gy vs. 1 time 8 Gy). A prospective study. Strahlenther Onkol 1999, 52, 101 109. 20 Wu JS, Wong R, Johnston M, Bezjak A, Whelan T. Cancer Care Ontario Practice Guidelines Initiative Supportive Care Group. Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys 2003, 55, 594~605. 21 Chow E, Ling A, Davis L, Panzarella T, Danjoux C. Pain flare following external beam radiotherapy and meaningful change in pain score in the treatment of bone metastases. Radiother Oncol 2005, 75, 64 69. 22 van der Linden Y, Lok JJ, Steeland E, et aL, for the Dutch Bone Metastasis Study Group. Single fraction radiotherapy is

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

95

efficacious: a further analysis of the Dutch Bone Metastasis Study controlling for the influence of retreatment. Int J Radiat Oncol Biol Phys 2004, 59, 528 537. Van den Hout WB, van der Linden YM, Steenland E, et al. Single- versus multiple-fraction radiotherapy in patients with painful bone metastases: cost-utility analysis based on a randomized trial. J Natl Cancer Inst 2003, 95, 2 2 2 2 2 9 . Shakespeare TP, Jiade JL, Back FB, Liang S, Mukherjee RK, Wynne CJ. Patient preference for radiotherapy fractionation schedule in the palliation of painful bone metastases. J Clin Oncol 2003, 21, 21562162. Szumacher A, Llewellyn-Thomas H, Franssen E, et al. Treatment of bone metastases with palliative radiotherapy: patients' treatment preference. Int J Radiat Oncol Biol Phys 2005, 5: 1473 1481. Roos DE, Turner SL, O' Brien PC¢t aL Randomized trial of 8 Gy in 1 versus 20 Gy in 5 fractions of radiotherapy for neuropathic pain due to bone metastases (Trans-Tasman Radiation Oncology Group, TROG 96.05). Radiother Oncol 2005, 75, 54 63. Rades D, Stalpers LJA, Veninga T, et al. Evaluation of five radiation schedules and prognosis factors for metastatic spinal cord compression. J Clin Oncol 2005, 23, 3366 3375. Rades D, Stalpers LJA, Hulshof MCCM, Zschenker O, Alberti W, Koning CCE. Effectiveness and toxicity of singlefraction radiotherapy with 1 ×8 Gy for metastatic spinal cord compression. Radiother Oncol 2005, 75, 7 0 ~ 3 . Maranzano E, Bellavia R, Rossi R, et al. Short course versus split courseradiotherpay in metastatic spinal cord compression: results of a phase III, radomized, multicenter trial. J Clin Oncol 2005, 23, 3358 3365. Leigh BR, Kurtts TA, Mack CF, Matzner MB, Shimm DS. Radiation therapy for the palliation of multiple myeloma. Int J Radiat Oncol Biol Phys 1993, 25, 801 804. Adamietz IA, Schober C, Schulte RW, Peest D, Renner K. Palliative radiotherapy in plasma cell myeloma. Radiother Oncol 199, 20, 111 116. Aronson SM, Garcia JH, Aronson BE. Metastatic neoplasms of the brain: their frequency in relation to age. Cancer 1964, 17, 558 563. Marcou Y, Lindquist C, Adams C, Retsas S, Plowman PN. What is the optimal therapy of brain metastases? Clin Oncol (R Coll Radiol) 2001, 13, 105 11. Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997, 37, 745 751. Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, Markesbery WR, Macdonald JS, Young B. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J M e d 1990, 322, 494-500. Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the treatment of single metastases to the brain. NEngl J M e d 1990, 322, 494-500. Engenhart R, Kimmig BN, Hover KH, et al. Long-term follow-up for brain metastases treated by percutaneous stereotactic single high-dose irradiation. Cancer 1993, 71, 1353 1361. Shaw RR, Paulson DL, Kee JLJ. Treatment of the superior sulcus tumor by irradiation followed by resection. Ann Surg 1961, 154: 29-36. Johnson DE, Goldberg M. Management of carcinoma of the superior pulmonary sulcus. Oncology (Huntingt) 1997, 11:781 785.

96

J . E N e b b i a e t aL

40 Jones DR, Detterbeck FC. Pancoast tumors of the lung. Curr Opin Pulm M e d 1998, 4:191 197. 41 Morganti AG, Trodella L, Valentini V, et al. Pain relief with shortterm irradiation in locally advanced carcinoma of the pancreas. J P a l l i a t Care 2003, 19, 258 262. 42 Van Heek NT, van Geenen RC, Busch OR, Gouma DJ. Palliative treatment in "peri"-pancreatic carcinoma: stenting or surgical therapy? Acta Gastroenterol Belg 2002, 65, 171 175. 43 Ma HB, Di ZL, Wang XJ, Kang HF, Deng HC, Bai MH. Effect of intraoperative radiotherapy combined with external beam radiotherapy following internal drainage for advanced pancreatic carcinoma. World J Gastroenterol 2004, 10, 1669 1771. 44 Moertel CG, Frytak S, Hahn RG, et al. Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group. Cancer 1981, 48, 1705 1710. 45 Crane C, Janjan N, Evans D, et al. Toxicity and efficacy of concurrent gemcitabine and radiotherapy for locally advanced pancreatic cancer. Int J Gastrointest Cancer 2001, 29, 9-18. 46 Laing AH, Ackery DM, Bayly RJ, et al. Strontium-89 chloride

47

48

49

50

51

for pain palliation in prostatic skeletal malignancy. Br J R a d i o l 1991, 64, 816 822. Lewington VJ, McEwan AJ, Ackery DM, et al. A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone. Eur J Cancer 1991, 27, 954 958. Porter AT, McEwan AJ, Powe JE, et al. Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J R a d i a t Oncol Biol Phys. 1993, 25, 805 813. Serafini AN, Houston S J, Resche I, et al. Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial. J Clin Oncol 1998, 16, 1574 1581. Salazar OM, DaMotta NW, Bridgman SM, Cardiges NM, Slawson RG. Fractionated half-body irradiation for pain palliation in widely metastatic cancers: comparison with single dose. Int J Radiat Oncol Biol Phys 1996, 36, 49-60. Pene F, Schlienger M, Schmitt T, et al. Half-body irradiation for pain relief. Eur J Cancer Clin Oncol 1981, 17, 753~58.